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Basil T Darras - One of the best experts on this subject based on the ideXlab platform.

  • Nusinersen treatment in adults with spinal muscular atrophy
    Neurology: Clinical Practice, 2021
    Co-Authors: Tina Duong, Basil T Darras, Connie Wolford, Michael P Mcdermott, Chelsea Macpherson, Amy Pasternak, Allan M Glanzman, William B Martens, Elizabeth Kichula, Darryl C. De Vivo
    Abstract:

    Abstract: Purpose To determine change in motor function after treatment with Nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability. Recent Findings All forty-two adult SMA patients (mean age: 34 years, range 17-66) receiving Nusinersen at PNCR sites were assessed for a mean of 12.5 months (range 3-24 months). Data collected prospectively generated a mean annual rate of change over time determined using linear mixed effects models. Motor and ventilatory measures showed positive changes distinct from the progressive decline expected in untreated adults. All participants tolerated Nusinersen with normal surveillance labs and no significant adverse events. Summary Trends of improvement in functional motor, patient-reported, and ventilatory measures, suggested Nusinersen benefit in adults with SMA, including the chronic, weaker phenotype. Longer duration and larger studies are needed to more firmly establish Nusinersen efficacy in adults with SMA.

  • Nusinersen improves walking distance and reduces fatigue in later onset spinal muscular atrophy
    Muscle & Nerve, 2019
    Co-Authors: Jacqueline Montes, Richard S. Finkel, Basil T Darras, Eugenio Mercuri, Amy Pasternak, Allan M Glanzman, Sally Dunaway Young, E Mazzone, Francesco Muntoni, Darryl C. De Vivo
    Abstract:

    INTRODUCTION Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with Nusinersen, but its impact on fatigue has not been studied. METHODS Post hoc analyses were used to examine changes in 6-minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of Nusinersen in the phase Ib/IIa, open-label CS2 study and were ambulatory during CS2 or the extension study, CS12. RESULTS Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by -3.8% (-19.7%, 1.4%). DISCUSSION These results support previous studies demonstrating clinically meaningful effects of Nusinersen on motor function in children and adolescents with later-onset SMA.

  • An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials
    CNS Drugs, 2019
    Co-Authors: Basil T Darras, Richard S. Finkel, Michelle A. Farrar, Eugenio Mercuri, Richard Foster, Steven G. Hughes, Ishir Bhan, Wildon Farwell, Sarah Gheuens
    Abstract:

    Background Treatment with Nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA). Objective The objective of this analysis was to characterize the safety of Nusinersen across the clinical trial program in infants and children with symptomatic SMA. Methods An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal Nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms. Results Data were analyzed from 323 infants and children, including 240 treated with Nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to Nusinersen was 449.0 (6–1538) days (375.9 participant-years). The most common AEs with Nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with Nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in Nusinersen- versus sham procedure–treated participants. Rates of post–lumbar puncture syndrome and related events were higher with Nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed. Conclusions Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures. Registration NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.

  • an integrated safety analysis of infants and children with symptomatic spinal muscular atrophy sma treated with Nusinersen in seven clinical trials
    CNS Drugs, 2019
    Co-Authors: Basil T Darras, Richard S. Finkel, Michelle A. Farrar, Eugenio Mercuri, Richard Foster, Steven G. Hughes, Ishir Bhan, Wildon Farwell, Sarah Gheuens
    Abstract:

    Treatment with Nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA). The objective of this analysis was to characterize the safety of Nusinersen across the clinical trial program in infants and children with symptomatic SMA. An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal Nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms. Data were analyzed from 323 infants and children, including 240 treated with Nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to Nusinersen was 449.0 (6–1538) days (375.9 participant-years). The most common AEs with Nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with Nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in Nusinersen- versus sham procedure–treated participants. Rates of post–lumbar puncture syndrome and related events were higher with Nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed. Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures. NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.

  • Nusinersen in later onset spinal muscular atrophy long term results from the phase 1 2 studies
    Neurology, 2019
    Co-Authors: Basil T Darras, Jacqueline Montes, Claudia A. Chiriboga, Kathryn J Swoboda, Susan T Iannaccone, Frank C Bennett, Kathie M Bishop, Laurence Mignon, Jeremy M Shefner, Allison M Green
    Abstract:

    Objective To report results of intrathecal Nusinersen in children with later-onset spinal muscular atrophy (SMA). Methods Analyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received Nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2–15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196–413 days). Assessments included the Hammersmith Functional Motor Scale–Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed. Results Twenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events. Conclusions Nusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of Nusinersen in later-onset SMA, including SMA type III. Clinicaltrials.gov identifier NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12). Classification of evidence This study provides Class IV evidence that Nusinersen improves motor function in children with later-onset SMA.

Claudia A. Chiriboga - One of the best experts on this subject based on the ideXlab platform.

  • treatment of infantile onset spinal muscular atrophy with Nusinersen final report of a phase 2 open label multicentre dose escalation study
    The Lancet Child & Adolescent Health, 2021
    Co-Authors: John W. Day, Darryl C. De Vivo, Jacqueline Montes, Claudia A. Chiriboga, Jiri Vajsar, Kathie M Bishop, Richard Foster, R Finkel, Yingying Liu
    Abstract:

    Summary Background Nusinersen showed a favourable benefit–risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of Nusinersen over 3 years. Methods This phase 2, open-label, multicentre, dose-escalation study was done in three university hospital sites in the USA and one in Canada. Infants aged between 3 weeks and 6 months with two or three SMN2 gene copies and infantile-onset spinal muscular atrophy were eligible for inclusion. Eligible participants received multiple intrathecal loading doses of 6 mg equivalent Nusinersen (cohort 1) or 12 mg dose equivalent (cohort 2), followed by maintenance doses of 12 mg equivalent Nusinersen. The protocol amendment on Jan 25, 2016, changed the primary efficacy endpoint from safety and tolerability to reaching motor milestones, assessed using the Hammersmith Infant Neurological Examination section 2 (HINE-2) at the last study visit, in all participants who successfully completed the loading dose period and day 92 assessment. The statistical analysis plan was amended on Feb 10, 2016, to include additional analyses of the subgroup of participants with two SMN2 copies. Adverse events were assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov ( NCT01839656 ). Findings Between May 3, 2013, and July 9, 2014, 20 symptomatic participants with infantile-onset spinal muscular atrophy (12 boys and 8 girls; median age at diagnosis 78 days [range 0–154]) were enrolled. Median time on study was 36·2 months (IQR 20·6–41·3). The primary endpoint of an incremental improvement in HINE-2 developmental motor milestones was reached by 12 (63%) of 19 evaluable participants. In the 13 participants with two SMN2 copies treated with 12 mg Nusinersen, the HINE-2 motor milestone total score increased steadily from a baseline mean of 1·46 (SD 0·52) to 11·86 (6·18) at day 1135, representing a clinically significant change of 10·43 (6·05). At study closure (Aug 21, 2017), 15 (75%) of 20 participants were alive. 101 serious adverse events were reported in 16 (80%) of 20 participants; all five deaths (one in cohort 1 and four in cohort 2) were likely to be related to spinal muscular atrophy disease progression. Interpretation Our findings are consistent with other trials of Nusinersen and show improved survival and attainment of motor milestones over 3 years in patients with infantile-onset spinal muscular atrophy, with a favourable safety profile. Funding Biogen and Ionis Pharmaceuticals.

  • Nusinersen in later onset spinal muscular atrophy long term results from the phase 1 2 studies
    Neurology, 2019
    Co-Authors: Basil T Darras, Jacqueline Montes, Claudia A. Chiriboga, Kathryn J Swoboda, Susan T Iannaccone, Frank C Bennett, Kathie M Bishop, Laurence Mignon, Jeremy M Shefner, Allison M Green
    Abstract:

    Objective To report results of intrathecal Nusinersen in children with later-onset spinal muscular atrophy (SMA). Methods Analyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received Nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2–15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196–413 days). Assessments included the Hammersmith Functional Motor Scale–Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed. Results Twenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events. Conclusions Nusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of Nusinersen in later-onset SMA, including SMA type III. Clinicaltrials.gov identifier NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12). Classification of evidence This study provides Class IV evidence that Nusinersen improves motor function in children with later-onset SMA.

  • Darras et al. NEUROLOGY/2018/918938 Supplementary appendix
    2019
    Co-Authors: Basil T Darras, Jacqueline Montes, Claudia A. Chiriboga, Kathryn J Swoboda, Susan T Iannaccone, Frank C Bennett, Kathie M Bishop, Laurence Mignon, Shuting Xia, Jeremy M Shefner
    Abstract:

    Supplementary appendix containing additional methodological details for the manuscript titled "Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies

  • Nusinersen versus sham control in later onset spinal muscular atrophy
    The New England Journal of Medicine, 2018
    Co-Authors: Eugenio Mercuri, Claudia A. Chiriboga, Basil T Darras, Susan T Iannaccone, Anne M Connolly, Craig Campbell, Janbernd Kirschner, Nancy L Kuntz, Kayoko Saito, Perry B Shieh
    Abstract:

    Abstract Background Nusinersen is an antisense oligonucleotide drug that modulates pre–messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). Methods We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of Nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of Nusinersen at a dose of 12 mg (Nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates impro...

  • Nusinersen versus sham control in infantile onset spinal muscular atrophy
    The New England Journal of Medicine, 2017
    Co-Authors: Richard S. Finkel, Claudia A. Chiriboga, Basil T Darras, Eugenio Mercuri, Laurent Servais, Anne M Connolly, Janbernd Kirschner, Nancy L Kuntz, Kayoko Saito, Eduardo F Tizzano
    Abstract:

    BackgroundSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonu...

Jacqueline Montes - One of the best experts on this subject based on the ideXlab platform.

  • treatment of infantile onset spinal muscular atrophy with Nusinersen final report of a phase 2 open label multicentre dose escalation study
    The Lancet Child & Adolescent Health, 2021
    Co-Authors: John W. Day, Darryl C. De Vivo, Jacqueline Montes, Claudia A. Chiriboga, Jiri Vajsar, Kathie M Bishop, Richard Foster, R Finkel, Yingying Liu
    Abstract:

    Summary Background Nusinersen showed a favourable benefit–risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of Nusinersen over 3 years. Methods This phase 2, open-label, multicentre, dose-escalation study was done in three university hospital sites in the USA and one in Canada. Infants aged between 3 weeks and 6 months with two or three SMN2 gene copies and infantile-onset spinal muscular atrophy were eligible for inclusion. Eligible participants received multiple intrathecal loading doses of 6 mg equivalent Nusinersen (cohort 1) or 12 mg dose equivalent (cohort 2), followed by maintenance doses of 12 mg equivalent Nusinersen. The protocol amendment on Jan 25, 2016, changed the primary efficacy endpoint from safety and tolerability to reaching motor milestones, assessed using the Hammersmith Infant Neurological Examination section 2 (HINE-2) at the last study visit, in all participants who successfully completed the loading dose period and day 92 assessment. The statistical analysis plan was amended on Feb 10, 2016, to include additional analyses of the subgroup of participants with two SMN2 copies. Adverse events were assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov ( NCT01839656 ). Findings Between May 3, 2013, and July 9, 2014, 20 symptomatic participants with infantile-onset spinal muscular atrophy (12 boys and 8 girls; median age at diagnosis 78 days [range 0–154]) were enrolled. Median time on study was 36·2 months (IQR 20·6–41·3). The primary endpoint of an incremental improvement in HINE-2 developmental motor milestones was reached by 12 (63%) of 19 evaluable participants. In the 13 participants with two SMN2 copies treated with 12 mg Nusinersen, the HINE-2 motor milestone total score increased steadily from a baseline mean of 1·46 (SD 0·52) to 11·86 (6·18) at day 1135, representing a clinically significant change of 10·43 (6·05). At study closure (Aug 21, 2017), 15 (75%) of 20 participants were alive. 101 serious adverse events were reported in 16 (80%) of 20 participants; all five deaths (one in cohort 1 and four in cohort 2) were likely to be related to spinal muscular atrophy disease progression. Interpretation Our findings are consistent with other trials of Nusinersen and show improved survival and attainment of motor milestones over 3 years in patients with infantile-onset spinal muscular atrophy, with a favourable safety profile. Funding Biogen and Ionis Pharmaceuticals.

  • Nusinersen in pediatric and adult patients with type iii spinal muscular atrophy
    Annals of clinical and translational neurology, 2021
    Co-Authors: Maria Carmela Pera, Jacqueline Montes, V Sansone, Tina Duong, Amy Pasternak, Sally Dunaway Young, Marika Pane, Giorgia Coratti, Francesca Bovis, Sonia Messina
    Abstract:

    Objective We report longitudinal data from 144 type III SMA pediatric and adult patients treated with Nusinersen as part of an international effort. Methods Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after Nusinersen treatment. Results Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. Interpretation Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

  • evaluation of Nusinersen on impact of caregiver experience and hrqol in later onset spinal muscular atrophy sma results from the phase 3 cherish trial 1429
    Neurology, 2020
    Co-Authors: Nicole B Johnson, Jacqueline Montes, Angela D Paradis, S Naoshy, Janice Wong, Debra C Krasinski
    Abstract:

    Objective: The objective of this study was to compare health-related quality of life (HRQoL) from the Phase 3 CHERISH trial among Nusinersen vs. sham-controlled patients. Background: SMA is a rare genetic disease characterized by degeneration of motor neurons resulting in progressive muscular weakness and atrophy. Limited data exists on the impact of SMA therapies on HRQoL. Design/Methods: Data from CHERISH, a randomized, double-blind, multicenter, sham-controlled clinical trial of later-onset SMA (most likely to develop SMA Type II or III) were analyzed. The exploratory endpoint of HRQoL was assessed using both the Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) administered at screening and Days 169 (Month 6) and 456 (Month 15), and the Pediatric Quality of Life Inventory (PedsQL), administered at several timepoints from screening to Month 15. ANCOVA modeling was used to analyze least squares (LS) mean change from baseline through Month 15. Results: The impact for caregivers was reduced in three out of seven domains of the ACEND in the Nusinersen group at Months 6 and 15; feeding/grooming/dressing, transfer, and mobility. The impact on caregivers was increased in these domains for the sham group at both assessments. The greatest reduction for caregivers was in the mobility domain: LS mean difference (95%) from baseline to Month 15 of Nusinersen vs. sham was 11.9 (3.9, 19.8). Continued reductions in the impact of caregivers were found with longer time on Nusinersen vs. sham in many domains. Results also showed improvements in PedsQL for Nusinersen vs. sham for both patient and parent assessments. For example, the LS mean difference for Nusinersen vs. sham from baseline to Month 15 was 5.0 (0.7, 9.3) for the parent assessment. Conclusions: Treatment with Nusinersen was associated with reducing the impact on caregivers and improvements in HRQoL over sham control in later-onset SMA patients. Study Supported by: Biogen Disclosure: Dr. Johnson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Johnson holds stock and/or stock options in Biogen. Dr. Paradis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Paradis holds stock and/or stock options in Holds stock/stock options in Biogen. Dr. Naoshy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Naoshy holds stock and/or stock options in Holds stock/stock options in Biogen. Dr. Wong has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Montes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for Biogen, Cytokinetics, Roche, Scholar Rock, and SMA Foundation; consultant for Biogen and Ionis Pharmaceuticals, Inc.; research support from Eunice Kennedy Shriver National Institute for Child Health and Human Development and Muscular D. Dr. Montes has received research support from Research support from Eunice Kennedy Shriver National Institute for Child Health and Human Development and Muscular Dystrophy Association. Dr. Krasinski has nothing to disclose.

  • Nusinersen improves walking distance and reduces fatigue in later onset spinal muscular atrophy
    Muscle & Nerve, 2019
    Co-Authors: Jacqueline Montes, Richard S. Finkel, Basil T Darras, Eugenio Mercuri, Amy Pasternak, Allan M Glanzman, Sally Dunaway Young, E Mazzone, Francesco Muntoni, Darryl C. De Vivo
    Abstract:

    INTRODUCTION Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with Nusinersen, but its impact on fatigue has not been studied. METHODS Post hoc analyses were used to examine changes in 6-minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of Nusinersen in the phase Ib/IIa, open-label CS2 study and were ambulatory during CS2 or the extension study, CS12. RESULTS Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by -3.8% (-19.7%, 1.4%). DISCUSSION These results support previous studies demonstrating clinically meaningful effects of Nusinersen on motor function in children and adolescents with later-onset SMA.

  • Nusinersen in later onset spinal muscular atrophy long term results from the phase 1 2 studies
    Neurology, 2019
    Co-Authors: Basil T Darras, Jacqueline Montes, Claudia A. Chiriboga, Kathryn J Swoboda, Susan T Iannaccone, Frank C Bennett, Kathie M Bishop, Laurence Mignon, Jeremy M Shefner, Allison M Green
    Abstract:

    Objective To report results of intrathecal Nusinersen in children with later-onset spinal muscular atrophy (SMA). Methods Analyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received Nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2–15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196–413 days). Assessments included the Hammersmith Functional Motor Scale–Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed. Results Twenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events. Conclusions Nusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of Nusinersen in later-onset SMA, including SMA type III. Clinicaltrials.gov identifier NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12). Classification of evidence This study provides Class IV evidence that Nusinersen improves motor function in children with later-onset SMA.

Richard S. Finkel - One of the best experts on this subject based on the ideXlab platform.

  • Nusinersen improves walking distance and reduces fatigue in later onset spinal muscular atrophy
    Muscle & Nerve, 2019
    Co-Authors: Jacqueline Montes, Richard S. Finkel, Basil T Darras, Eugenio Mercuri, Amy Pasternak, Allan M Glanzman, Sally Dunaway Young, E Mazzone, Francesco Muntoni, Darryl C. De Vivo
    Abstract:

    INTRODUCTION Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with Nusinersen, but its impact on fatigue has not been studied. METHODS Post hoc analyses were used to examine changes in 6-minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of Nusinersen in the phase Ib/IIa, open-label CS2 study and were ambulatory during CS2 or the extension study, CS12. RESULTS Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by -3.8% (-19.7%, 1.4%). DISCUSSION These results support previous studies demonstrating clinically meaningful effects of Nusinersen on motor function in children and adolescents with later-onset SMA.

  • Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy interim efficacy and safety results from the phase 2 nurture study
    Neuromuscular Disorders, 2019
    Co-Authors: Darryl C. De Vivo, Richard S. Finkel, Kathryn J Swoboda, Thomas O Crawford, Janbernd Kirschner, Nancy L Kuntz, Julie Parsons, Enrico Bertini, Monique M Ryan, Russell J Butterfield
    Abstract:

    Abstract Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received Nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7–45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 hours/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to Nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with Nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

  • An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials
    CNS Drugs, 2019
    Co-Authors: Basil T Darras, Richard S. Finkel, Michelle A. Farrar, Eugenio Mercuri, Richard Foster, Steven G. Hughes, Ishir Bhan, Wildon Farwell, Sarah Gheuens
    Abstract:

    Background Treatment with Nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA). Objective The objective of this analysis was to characterize the safety of Nusinersen across the clinical trial program in infants and children with symptomatic SMA. Methods An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal Nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms. Results Data were analyzed from 323 infants and children, including 240 treated with Nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to Nusinersen was 449.0 (6–1538) days (375.9 participant-years). The most common AEs with Nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with Nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in Nusinersen- versus sham procedure–treated participants. Rates of post–lumbar puncture syndrome and related events were higher with Nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed. Conclusions Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures. Registration NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.

  • an integrated safety analysis of infants and children with symptomatic spinal muscular atrophy sma treated with Nusinersen in seven clinical trials
    CNS Drugs, 2019
    Co-Authors: Basil T Darras, Richard S. Finkel, Michelle A. Farrar, Eugenio Mercuri, Richard Foster, Steven G. Hughes, Ishir Bhan, Wildon Farwell, Sarah Gheuens
    Abstract:

    Treatment with Nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA). The objective of this analysis was to characterize the safety of Nusinersen across the clinical trial program in infants and children with symptomatic SMA. An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal Nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms. Data were analyzed from 323 infants and children, including 240 treated with Nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to Nusinersen was 449.0 (6–1538) days (375.9 participant-years). The most common AEs with Nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with Nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in Nusinersen- versus sham procedure–treated participants. Rates of post–lumbar puncture syndrome and related events were higher with Nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed. Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures. NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.

  • interim report on the safety and efficacy of longer term treatment with Nusinersen in infantile onset spinal muscular atrophy sma updated results from the shine study s25 004
    Neurology, 2019
    Co-Authors: Richard S. Finkel, Diana Castro, Michelle A. Farrar, Ishir Bhan, Wildon Farwell, Kayoko Saito, Már Tulinius, Kristin J Krosschell, Yiwei Zhang, Sandra P Reyna
    Abstract:

    Objective: To report interim results from the SHINE study (NCT02594124) for individuals with infantile-onset SMA (most likely to develop Type I) who transitioned from ENDEAR. Background: Nusinersen has demonstrated a favorable benefit:risk profile and shown significant and clinically meaningful efficacy on motor function across a broad spectrum of SMA populations and on event-free survival (EFS; time to death or permanent ventilation) in infantile-onset SMA. SHINE is an open-label extension study for infants/children who previously participated in Nusinersen clinical trials. Design/Methods: Nusinersen doses were initially administered according to participant’s previous trial cohort/regimen. The primary endpoint is safety/tolerability; secondary endpoints include achievement of HINE-2 motor milestones and EFS. Results: The cutoff date for the previous interim analyses was June 30, 2017; 89 infants transitioned from ENDEAR, 65/81 were previously randomized to Nusinersen and 24/41 to sham-control. Within SHINE only, 83 infants had an adverse event (AE). Infants who received sham-control in ENDEAR and Nusinersen in SHINE (n=20/24) and those who received Nusinersen in ENDEAR and SHINE (n=74/81; pooled ENDEAR/SHINE data) demonstrated continued improvements in HINE-2 total score from Nusinersen initiation to last observed visit (mean [95%CI] change: 1.1 [0.20–1.90] and 5.8 [4.58–7.04], respectively). Median (95%CI) EFS time among sham-control infants in ENDEAR was 22.6 (13.6–31.3) weeks vs 73.0 (36.3–NA) weeks for those who received Nusinersen in ENDEAR and SHINE. Results from an interim analysis with an October 15, 2018 cutoff date will be presented. Conclusions: At the time of the previous data cutoff, motor function and EFS continued to improve in infants who initiated Nusinersen in ENDEAR and motor function stabilized or started to show improvement in those who initiated Nusinersen in SHINE. Data from more recent analyses will provide additional information on the long-term efficacy and safety of Nusinersen in infantile-onset SMA. Disclosure: Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Castro has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for Marathon and Sarepta. Dr. Castro has received research support from Principal investigator for Biogen studies, Sarepta, ReveraGen and FibroGen. Dr. Farrar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Scientific advisory board honoraria from Biogen. Dr. Farrar has received research support from Research support from Motor Neuron Diseases Research Institute of Australia, Biogen grant, principal investigator for ongoing Biogen and AveXis clinical trials. Dr. Tulinius has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, and PTC. Dr. Tulinius has received research support from Ionis Pharmaceuticals, Inc./Biogen trials in Sweden. Dr. Krosschell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Cytokinetics, and Cure SMA. Dr. Krosschell has received research support from AveXis, Ionis, Biogen, and Cytokinetics. Dr. Saito has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen and Roche/Chugai. Dr. Saito has received research support from Biogen and Roche/Chugai for research consultation and from Ionis Pharmaceuticals Inc. for execution of clinical trial projects. Dr. Zhang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Zhang holds stock and/or stock options in Biogen. Dr. Bhan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Bhan holds stock and/or stock options in Biogen. Dr. Farwell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Farwell holds stock and/or stock options in Biogen. Dr. Reyna has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Reyna holds stock and/or stock options in Biogen.

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  • real world respiratory and bulbar comorbidities of sma type 1 children treated with Nusinersen 2 year single centre australian experience
    Paediatric Respiratory Reviews, 2021
    Co-Authors: Kerrieanne Chen, Michelle A. Farrar, John Widger, Arthur Teng, Dominic A Fitzgerald, Arlene Dsilva
    Abstract:

    Abstract Aim To describe the respiratory and nutritional supportive care and hospitalisations required in the real-world scenario in children with SMA type 1 treated with Nusinersen. Methods Single-centre observational cohort study of children with SMA1 commencing Nusinersen from November 2016 to September 2018. Motor, respiratory and nutritional clinical characteristics and management are described from initiation of Nusinersen for a minimum of two years. Results Nine children (5 females, 4 males), median age 10.7 months (range 2.7–181.2) commenced treatment with Nusinersen and outcomes were assessed over a total of 270.5 patient months and 209 hospital admissions. Supportive care in newly-diagnosed patients (n = 7) included gastrostomy insertion (n = 4) and commencement of noninvasive ventilation (n = 4) at an average of 8.3 and 4.5 months after diagnosis, respectively. The annualised hospitalisation rate was 9.3/patient/year, average length of stay (LOS) of 3.3 days (SD = 5.6). Children with two SMN2 copies required more gastrostomies (p  Interpretation Children with treated SMA1 experienced considerable respiratory and bulbar comorbidities, necessitating substantial respiratory and nutritional supportive care. Proactive respiratory and nutritional surveillance and management is essential in SMA1 patients treated with Nusinersen.

  • motor unit changes in children with symptomatic spinal muscular atrophy treated with Nusinersen
    Journal of Neurology Neurosurgery and Psychiatry, 2021
    Co-Authors: Didu Sanduni Kariyawasam, Karen Herbert, Arlene Dsilva, James Howells, Peter Geelansmall, Cindy S Y Lin, Michelle A. Farrar
    Abstract:

    Objectives To elucidate the motor unit response to intrathecal Nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique. Methods MScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with Nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%–100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50). Results Twenty children (median age 99 months, range 4–193) were followed for a median of 13.8 (4–33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (p Interpretation Nusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.

  • treating adults with spinal muscular atrophy with Nusinersen
    Journal of Neurology Neurosurgery and Psychiatry, 2020
    Co-Authors: Michelle A. Farrar, Matthew C Kiernan
    Abstract:

    Nusinersen was the first drug approved to treat people with spinal muscular atrophy (SMA), based on clinical data obtained from the initial trials undertaken in infants and children.1 2 With limited evidence of the safety and efficacy of Nusinersen across the spectrum of ages and severities in SMA, adult patients are now confronting uncertain therapeutic expectations, with associated difficulties in realising equitable access to treatment.3 4 In the paper by Maggi and colleagues5 in this issue of the journal, further evidence indicates that treatment with Nusinersen can be administered safely to adult patients with SMA, with clinically meaningful results obtained in a ‘real world’ setting. This Italian multicentre study included a …

  • An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials
    CNS Drugs, 2019
    Co-Authors: Basil T Darras, Richard S. Finkel, Michelle A. Farrar, Eugenio Mercuri, Richard Foster, Steven G. Hughes, Ishir Bhan, Wildon Farwell, Sarah Gheuens
    Abstract:

    Background Treatment with Nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA). Objective The objective of this analysis was to characterize the safety of Nusinersen across the clinical trial program in infants and children with symptomatic SMA. Methods An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal Nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms. Results Data were analyzed from 323 infants and children, including 240 treated with Nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to Nusinersen was 449.0 (6–1538) days (375.9 participant-years). The most common AEs with Nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with Nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in Nusinersen- versus sham procedure–treated participants. Rates of post–lumbar puncture syndrome and related events were higher with Nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed. Conclusions Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures. Registration NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.

  • an integrated safety analysis of infants and children with symptomatic spinal muscular atrophy sma treated with Nusinersen in seven clinical trials
    CNS Drugs, 2019
    Co-Authors: Basil T Darras, Richard S. Finkel, Michelle A. Farrar, Eugenio Mercuri, Richard Foster, Steven G. Hughes, Ishir Bhan, Wildon Farwell, Sarah Gheuens
    Abstract:

    Treatment with Nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA). The objective of this analysis was to characterize the safety of Nusinersen across the clinical trial program in infants and children with symptomatic SMA. An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal Nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms. Data were analyzed from 323 infants and children, including 240 treated with Nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to Nusinersen was 449.0 (6–1538) days (375.9 participant-years). The most common AEs with Nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with Nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in Nusinersen- versus sham procedure–treated participants. Rates of post–lumbar puncture syndrome and related events were higher with Nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed. Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures. NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.

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